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Pathological mechanisms underlying single large-scale mitochondrial DNA deletions

Lookup NU author(s): Dr Mariana Rocha, Hannah Rosa, Dr John Grady, Dr Langping He, Jane Newman, Professor Bobby McFarland, Dr Yi Ng, Dr Grainne Gorman, Dr Andrew Schaefer, Dr Helen Tuppen, Professor Robert Taylor, Professor Doug Turnbull

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2017 American Neurological Association Objective: Single, large-scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large-scale mtDNA deletions in skeletal muscle. Methods: We investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43 years) with characterized single, large-scale mtDNA deletions. Mitochondrial respiratory chain deficiency in skeletal muscle biopsies was quantified by immunoreactivity levels for complex I and complex IV proteins. Single muscle fibers with varying degrees of deficiency were selected from 6 patient biopsies for determination of mtDNA deletion level and copy number by quantitative polymerase chain reaction. Results: We have defined 3 “classes” of single, large-scale deletion with distinct patterns of mitochondrial deficiency, determined by the size and location of the deletion. Single fiber analyses showed that fibers with greater respiratory chain deficiency harbored higher levels of mtDNA deletion with an increase in total mtDNA copy number. For the first time, we have demonstrated that threshold levels for complex I and complex IV deficiency differ based on deletion class. Interpretation: Combining genetic and immunofluorescent assays, we conclude that thresholds for complex I and complex IV deficiency are modulated by the deletion of complex-specific protein-encoding genes. Furthermore, removal of mt-tRNA genes impacts specific complexes only at high deletion levels, when complex-specific protein-encoding genes remain. These novel findings provide valuable insight into the pathogenic mechanisms associated with these mutations. Ann Neurol 2018;83:115–130.


Publication metadata

Author(s): Rocha MC, Rosa HS, Grady JP, Blakely EL, He L, Romain N, Haller RG, Newman J, McFarland R, Ng YS, Gorman GS, Schaefer AM, Tuppen HA, Taylor RW, Turnbull DM

Publication type: Article

Publication status: Published

Journal: Annals of Neurology

Year: 2018

Volume: 83

Issue: 1

Pages: 115-130

Online publication date: 24/01/2018

Acceptance date: 21/12/2017

ISSN (print): 0364-5134

ISSN (electronic): 1531-8249

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.1002/ana.25127

DOI: 10.1002/ana.25127


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